Project Summary/Abstract There are approximately 50,000 people in the US with complete amputation of the hand, and many more with debilitating partial hand amputations. Treatments have not changed substantially since the body powered hook was invented during the civil war. While electrical signals from residual muscle can provide some function, every amputee is missing muscles, and therefore missing a variety of important functions. Attempts to record these signals from the nerves have suffered from low amplitude, low longevity, or both. Recently our group has demonstrated a novel method for obtaining signals from independent nerve fascicles in rats and NHPs, which we call the Regenerative Peripheral Nerve Interface (RPNI). Multiple dissected residual nerve branches are each placed in a 1x3 cm free muscle graft. The small muscle grafts degenerate, regenerate, revascularize, and reinnervate utilizing natural biologic processes. Upon completion of this regenerative process, the neurotized free muscle graft then amplifies a 5 ?V cuff ENG into a >250 ?V EMG signal. Most recently, we have replicated these results in 3 humans with upper limb amputation, routinely recording signals above 100 ?V that correspond to individual finger movements. Our long-term goal is to provide intuitive high fidelity control of individual prosthetic fingers and enable naturalistic sensory feedback. The objective of the present application, which represents our proposed next step, is a pilot clinical trial of safety and bidirectional prosthetic control efficacy using the RPNI in 6 subjects. Our team includes the original developers of the RPNI concept, Drs. Cederna and Kung, who have since placed human RPNI implants in 65 patients for the control of neuroma pain. The team also includes two engineers, Drs. Chestek and Gillespie with complementary expertise in neural signal processing and prosthetic control. Dr. Chestek also has extensive experience in neuroprosthetic human clinical trials. Three specific aims have been constructed to address independent aspects of safety and efficacy of RPNis in humans during a 5 year study. In Aim 1, 6 participants will be implanted with multiple grafts on each severed nerve, following by indwelling EMG electrodes in a later procedure. Multiple validated instruments will be used to monitor pain and other potential adverse events during this process. In Aim 2, we will evaluate the amplitude, specificity, and longevity of the result neural signals for up to 12 months. In Aim 3, we will quantitatively determine whether enhanced finger control ultimately enables higher performance on tasks of daily living and embodiment with the prosthetic limb. The results of these aims will provide critical safety and efficacy data, and strongly motivate a larger, perhaps pivotal clinical trial across multiple years, using a wireless implantable neural recording device for EMG.